Histones are the protein component of chromatin. Histones act to form DNA into coils with short lengths of DNA being wrapped around a histone core so that the DNA is supported by histone octamers to form nucleosomes. These histone proteins have lysine rich tails which when deacetylated become charged and attracted to the DNA backbone, causing the DNA to be wrapped around the histone core. This condensing of the chromatin structure means that proteins involved in gene transcription cannot gain access to the DNA, resulting in transcriptional repression or silencing. Histone deacetylase (HDAC) enzymes catalyses the deacetylation of the lysine tails; the inhibition of these enzymes rapidly leads to the acetylation of the lysine tails of histone, causing the chromatin to adopt an open conformation, enabling transcription of genes, especially genes that influence or maintain a diseased state when silenced.
A number of recent research reports suggest that chromosome translocations in cancer cells disrupt proteins involved in the process of histone acetylation and de-acetylation, and that these abnormal proteins cause aberrant gene repression.
It has been proposed that inhibition of histone deacetylase enzymes could relieve such gene repression and reinstate the program of differentiation and apoptosis in a manner analogous to the use of retinoic acid in the treatment of acute promyelocytic leukemia—a form of “transcription therapy”.
A number of compounds that inhibit HDAC have been described, and several are in phase I and II clinical trials. These compounds have been shown to induce cell cycle arrest, differentiation and cell death in cancer cells growing in vitro and in animal xenograft models.
The most potent HDAC inhibitor, Trichostatin A (TSA) was isolated from Streptomyces hygroscopicus in the 1970's, as an antifungal antibiotic against trichophyton. Although potent in vitro, TSA has limited stability and is therefore not therapeutically useful. Novel compounds with a similar structure, such as suberoylanilide hydroxamic acid (SAHA):
have activity in pre-clinical models, and have shown anti-cancer activity in clinical. However, this compound is also of limited stability and is rapidly eliminated, requiring large doses for activity. Other HDAC inhibitors that have been tested in the phase I setting show major side effects (e.g. Depsipeptide shows cardiac toxicity), or affect histone acetylation by an indirect mechanism (CI-994). Others are still undergoing early clinical investigation.
There is therefore a need for an HDAC inhibitor that is more potent and metabolically stable than SAHA.